GB2162171A

GB2162171A - Amidine compounds

Info

Publication number: GB2162171A
Application number: GB08419054A
Authority: GB
Inventors: Setsuro Fujii; Toyoo Nakayama; Shigeki Nunomura; Yojiro Sakurai; Masateru Kurumi; Takuo Aoyama; Kimio Sudo; Shin-Ichi Watanabe; Toshiyuki Okutome
Original assignee: Torii and Co Ltd
Current assignee: Torii and Co Ltd
Priority date: 1984-07-26
Filing date: 1984-07-26
Publication date: 1986-01-29
Also published as: GB2162171B; GB8419054D0

Abstract

The invention provides amidine compounds of the general formula <IMAGE> wherein A represents a furan, thiophene or benzofuran group; R1 represents a hydrogen atom or a straight or branched chain alkyl group of 1 to 4 carbon atoms; R2 represents a hydrogen atom, a straight or branched chain alkyl group of 1 to 4 carbon atoms, an acyl group or <IMAGE> in which R3, R4 and R5, any two of which may be the same or different, each represents a hydrogen atom or a strain or branched chain alkyl group of 1 to 4 carbon atoms; or either R1 and R2, when R2 does not represent a nitrogen containing radical, or any two or more of radicals R1, R3, R4 and R5, together with the nitrogen atoms to which they are attached, form a heterocyclic ring system, which may optionally contain other hetero atoms, and which may be unsubstituted or substituted; and n is 0, 1 or 2, and physiologically tolerable acid addition salts thereof, as well as processes for their preparation. The compounds are useful as powerful anti-trypsin, anti-plasmin, anti-kallikrein and anti-thrombin agents and are also useful as powerful anti-complement agents.

Description

SPECIFICATION Amidine Compounds The present invention provides novel amidino compounds of formula (I)

wherein A represents a furan, thiophene or benzofuran group; R1 represents a hydrogen atom or a straight or branched chain alkyl group of 1 to 4 carbon atoms; R2 represents a hydrogen atom, a straight or branched chain alkyl group of 1 to 4carbon atoms, an acyl group or

in which R3, R4 and R5, any two of which may be the same or different, each represents a hydrogen atom or a straight or branched chain alkyl group of 1 to 4 carbon atoms; or either R1 and R2, when R2 does not represent a nitrogen containing radical, or any two or more of radicals R1, R3, R4 and R5, together with the nitrogen atoms to which they are attached, form a heterocyclic ring system, which may optionally contain other hetero atoms, and which may be unsubstituted or substituted; and n is 0, 1 or 2, and salts, especially pharmaceutically acceptable acid addition salts, thereof.

In formula (I) R2 preferably represents

wherein R3, R4 and R5 are as defined above.

In formula (I) the acyl group represented by R2 is preferably R6-CO-, wherein Re represents a straight or branched chain alkyl group of 1 to 15 carbon atoms, a straight or branched chain alkoxy group of 1 to 4 carbon atoms, benzyloxy,

in which R7 and R8, which may be the same or different, each represents a hydrogen atom, a straight or branched chain alkvl group of 1 to 4 carbon atoms, benzvloxvcarbonvl or another amino- protecting group, B represents

in which m is 1 or 2, and Rg represents

In formula (I) Ais preferablyfuran.

It is possible for R1 and R2 to form a ring with the nitrogen atom to which they are attached to provide, for example, a

group or a complex hereto ring system depending on the meaning of R2. It is preferred, however, that ring systems are formed from the radicals R1 and R2, when R2 does not represent a nitrogen-containing radical, or from the radicals R3, R4 andíor R5, with R, representing a hydrogen atom in the latter case.

Where a heterocyclic ring system is present in a compound of the present invention, it will contain at least one nitrogen atom and may also optionally contain, for example, an oxygen or additional nitrogen atom. It may be unsubstituted or substituted. Substituents of such a hetero system may occur at any free member in the system, but preferably substitute a free ring nitrogen atom; there may be one or more of the same or different substituents in the ring system. Preferably substituents are selected from straight or branched chain alkyl groups of 1 to 4 carbon atoms and benzyl groups. Free ring nitrogen atoms may be substituted by any of the customary amino protecting groups.

Compounds of the invention have powerful anti-trypsin, anti-plasmin, anti-kallikrein and anti-thrombin activities and also an anti-complement activity.

Compounds of this invention may be produced by the reaction between a carboxylic acid compound of the formula (II) our a reactive intermediate or salt thereof and 6-amidino-2-naphthol of the formula (III) or preferably an acid addition salt thereof.

R1, R2, A and n are as defined above. The reactive intermediates, as herein referred to, include acid halides and acid anhydrides commonly used in dehydration condensation and the reactive intermediates formed by reacting for example dicyclohexyl carbodiimide (DCC) or diphenyl phosphorylazide (DPPA) with a carboxylic acid derivative.

Processes for producing compounds of the present invention are described below in detail by way of example only.

A compound (I) of the present invention can be prepared by dissolving or suspending a carboxylic acid compound (II) in an organic solvent such as dimethylformamide or pyridine, then allowing the compound (II) to react with a carboxylic acid activator such as dicyclohexylcarbodiimide (DCC) or diphenylphosphoryl azide (DPPA), which is usually used as dehydration-condensation agent, and adding 6-amidino-2-naphthol (III) or preferably an acid addition salt thereof to the reaction product.

For instance when DCC is used as the dehydration-condensation agent, a carboxylic acid derivative (II) may be added to a solvent such as pyridine, then 6-amidino-2-naphthol (III) is added, and the mixture is stirred at a temperature from -30" to 80"C, preferably at room temperature, for 3 to 5 hours to complete the reaction, though it is not objectionable to continue the reaction overnight. Dicyclohexylurea (DCU) precipitates out of the reaction mixture, while the compound (I) of the invention either precipitates with DCU or remains dissolved in the solvent In the former case, both precipitates may be collected by filtration, then suspended in a suitable solvent such as dimethylformamide (DMF) and the mixture filtered to remove insoluble DCU.After adding to the filtrate a solvent such as ethyl ether (i.e. diethyl ether), ethyl acetate or acetone, the precipitate may be collected by filtration to obtain the compound (I). Alternatively, the combined precipitate of DCU and the compound (I) may be collected by filtration, then added to a suitable solvent such as dimethylformamide or water to remove insoluble DCU by filtration, and the filtrate is added to a saturated aqueous sodium hydrogen carbonate solution to obtain the compound (I) in the form of the carbonate. In the latter case, where the compound (I) remains dissolved in the reaction mixture, DCU may be removed by filtration and the filtrate is admixed with a solvent such as ethyl ether, acetone or ethyl acetate to obtain a compound (I) of the present invention.

In another process, for example, when it is intended to use an acid halide as a reactive intermediate of a carboxylic acid derivative (II), the latter derivative (II) is allowed to react with an acid halogenation agent such as SOCI2, SOBr2 or PCl5to synthesize an acid halide represented by the formula (IV)

wherein R1, R2, A and n are as defined above and X represents a halogen atom. The acid halide may be added to a solution of 6-amidino-2-naphthol (III), preferably in the form of an acid addition salt, dissolved in for example dimethylformamide, pyridine or dimethyl sulfoxide, and allowed to react in the presence of a dehydrohalogenation agent.The dehydrohalogenation agents which can be used include inorganic bases such as potassium carbonate, sodium carbonate and sodium hydroxide and organic bases such as triethylamine, pyridine and dimethylaniline. Of these bases, pyridine is preferred. Although the reaction proceeds readily at a temperature in the range of from -30" to 80"C, it is preferable for the purpose of avoiding side reactions to conduct the reaction in the early stage under ice cooling and then at room temperature. The reaction is generally complete in 2 to 5 hours, though the reaction mixture can be left overnight. After completion of the reaction, the reaction mixture is treated in a customary manner.For instance, when pyridine is used as the reaction medium, a solvent such as ethyl ether or ethyl acetate may be added to the reaction mixture to precipitate a solid reaction product which is then recrystallized from a suitable solvent such as methanol-ethyl ether mixture to obtain a compound (I) of the present invention.

The compound (III) may be replaced by the corresponding compound wherein the amidino group is protected, and the latter compound can be allowed to react with the compound (II) or reactive intermediate or salt to obtain the compound (I) wherein the amidino goup is protected. Splitting off an amidino protecting group in a usual manner can yield a compound (I) of the present invention.

The present invention also provides a compound of the formula (I) in which the or each amidino group present is protected.

The amidino protecting group may be a conventionally used one. Examples thereof include a benzyloxycarbonyl or t-butoxycarbonyl group. Examples of a method for splitting off an amidino protecting group include reductive elimination by palladiumcarbon or elimination by trifluoroacetic acid or HBr/acetic acid. Such groups may be used to protect the free amidino group attached to the naphthyl group in the compound (I) and/or to protect a free amidino group represented by amidino group R2, when R3, R4 and R5 all represent hydrogen, or amidino group R6, when R2 represents an acyl group R6CO-.

Further, if desired, a compound (I) of the present invention can be prepared in the corresponding reduced form by the reduction of a suitable compound of formula (I) by use of a suitable reducing agent. For example, a compound of formula (I) having a nitro group is converted into a compound of formula (I) having an amino group by reduction.

Still further, if desired, a compound of the present invention can be obtained by the removal of protective groups of amino or amidino. The protective groups, as herein referred to, include those which are commonly used, such as, for example, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl and tert-butyl groups. For instance, a compound having an aminomethyl group may be obtained by the removal of the protective group from a compound having a benzyloxycarbonylaminomethyl group.

If necessary, acid addition salts of the compounds of the present invention may be prepared in customary manner. For instance, the carbonate of a compound (I) is dissolved or suspended in a solvent such as methanol or DMF and the carbonate is allowed to dissolve by the addition of an acid such as methanesulfonic acid or hydrochloric acid. To the resulting solution is added a solvent such as ethyl ether or ethyl acetate to obtain a corresponding acid addition salt. Acids which can be used for example are pharmaceutically acceptable ones including inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as acetic acid, lactic acid, citric acid, methanesulfonic acid, succinic acid, fumaric acid and maleic acid.

The present compounds and the pharmaceutically acceptable acid addition salts thereof possess powerful inhibitory activities against proteases, that is, trypsin, plasmin, kallikrein and thrombin, and are effective as anti-trypsin agents for the treatment of pancreatitis, as anti-plasmin or anti-kallikrein agents for hemorrhagenic diseases, and as anti-thrombin agents for thrombus.

With respect to the above-mentioned proteases, their roles in the living body, the relationship to the diseases, the clinical significance of these proteases inhibitors and the significance of the tests herein performed are explained below: I. Trypsin: Trypsin is a protease existing originally in the form of proenzymetrypsinogen in the pancreas and the proenzyme is secreted into the small intestine where it is transformed into trypsin by activation with enterokinase existing therein. Trypsin has a role as one of the digestive enzymes. If the trypsinogen is activated by any chance in the pancreas to form trypsin, the pancreas tissue will be injured to manifest clinically the symptoms of pancreatitis.In fact, it is known that in an experiment using the rat as test animal, when trypsin is injected conversely into the pancreas, the onset of intense pancreatitis is observed but the disease is cured by the administration of a trypsin inhibitor. From this fact, it can be presumed that a compound of the present invention having a strong trypsin inhibitory activity is useful as an anti-trypsin agent which is clinically effective for the treatment of pancreatitis.

II. Plasmin: Plasmin is an enzyme existing in the blood, usually in the form of proenzyme plasminogen which is converted to plasmin by activation with a plasminogen tissue activator such as urokinase. This enzyme acts reversely to the action of thrombin, that is, it acts to dissolve fibrin. For this reason, piasmin plays an important role in securing blood flow through capillaries. However, when this enzyme becomes abnormally activated for some reason, it causes hemorrhagenic diseases. This enzyme participates also in inflammation, increasing the vascular permeability and causing edema orthe like. Therefore, an inhibitor for this enzyme is useful as a drug to treat hemorrhagenic diseases and inflammation.

III. Kallikrein: Kallikrein is an enzyme widely distributed in blood and other organs and glands, usually in the form of its precursor prekallikrein which is activated with Hageman factor or other proteases. This enzyme participates in the hypotensive kallikrein-kinin system which counteracts the hypertensive renin-angitotensin system and plays an important role in the control of blood pressure. This enzyme participates also in the exogenous coagulation system. Further, kallikrein originated from organs or glands plays an important role in the improvement of local circulation. However, an abnormal activation, particularly an abnormal local activation, of this enzyme causes an insufficiency of local circulation due to the exaggeration of the coagulation system, causing for example inflammation or ulcer.Therefore, a kallikrein inhibitor is useful for the control of blood pressure and as a drug for the treatment of inflammation or ulcers.

IV. Thrombin: Thrombin is known as an enzyme having a blood coagulating activity. In the normal state, thrombin is formed by the activation of prothrombin in the blood when the vascular wall is injured.

Thrombin acts to decompose thefibrinogen in the blood into fibrin. The resulting fibrin deposits on the injured part of the vascular wall to prevent plasma components from transudation and simultaneously to promote the restoration of tissues. However, when the coagulation system is abnormally activated for some reason, a large number of fine thrombi are formed in capillaries throughout the entire body. Therefore, the present compounds are useful as drugs for the treatment of such a disease.

The present compounds and their pharmaceutically acceptable acid addition salts possess a strong Cl esterase (Clr, Cls) inhibitory activity, an ability to inhibit the complement mediated hemolysis, and a therapeutic activity against the Forssman shock in which the activation of the complement system caused by an immune complex is said to play an important role. This indicates that the present compounds are useful as anti-complement agents effective for the treatment of allergenic diseases such as nephritis associated with the complement.

The role of complement in the living body, the interrelation between a disease and the complement, the clinical significance of inhibitor, and the significance of tests (inhibition of Clr, Cls, complement mediated hemolysis, and forssman shock) performed by the present inventors are described below.

Anti-complement activity: (1) Clr,Cls The complement is one of the serum components and comprises 9 components of CI to C9. CI is separated into 3 subcomponents of Clq, CIr and Cls. CIs and Cl? means activated CIs and activated Clr, respectively. The complement was thought at first to perform a part in the infection protective process of the living body, since it shows bacteriolysis, but recently an intimate relation to immunity has been evident. It was shown that the complement is activated by the immune complex progressively from Cl to C9 and exhibits cytolysis or hemolysis at the final stage (activation of C9). It was also disclosed that the fragments (e.g.C3a, C5a) liberated in the course of activation of the complement system exaggerate the vascular permeability and promote the chemotaxis of polymorphonuclear leucocytes or immune adherence. Since that time, the interrelationship between the abnormal activation of complement and various diseases, particularly immune diseases, has been extensively investigated and, as a result, the intimate association of autoimmune diseases with the complement is beginning to be disclosed. Examples of autoimmune diseases caused by the abnormal activation of complement include antoimmune hemolytic anemia, autoimmune thrombocytopenia, leukopenia, glomeruionephritis, systemic lupus erythematosus, serum sickness and periarteritis nodosa. It is thought that such diseases might be cured by inhibiting the activation of complement or inhibiting the activated complement in an early stage.The present inventors examined the CI esterase inhibitory effect of the present compounds by using CI esterase as target enzyme and, in addition, the influenceof the present compounds on the complement system to estimate the usefulness of the present compounds as drugs for the treatment of autoimmune diseases.

(2) Complement mediated hemolysis: The complement mediated hemolysis is widely used as a means to determine the titration of complement.

The principle of this method is based on the fact that hemolysis is caused by the activation of complement, when the latter is added to a complex (immune complex) of erythrocytes and the antibody thereof. The degree of hemolysis varies in proportion to the amount of complement added. Therefore, when a known amount of complement admixed with a CI esterase inhibitor is used, the hemolysis must be suppressed in proportion to the inhibitory activity. The present compounds having CI esterase inhibitory activity showed strong inhibition of complement mediated hemolysis as shown hereinafter.

(3) Forssman shock.

Quite unlike other animals, the guinea pig has on the surface of its organs a specific antigen called Forssman antigen which specifically reacts with the antibody of sheep erythrocyte. Forssman shock is based on the above principle and is a shock caused by the administration of antibody of sheep erythrocyte to a guinea pig. The Forssman shock was investigated in detail by many researchers and it was definitely shown that this shock is a model case where the complement plays the principal part and that the shock is associated with a classical pathway in which the complement system is activated progressively starting from Cl. Since the participation of complement in autoimmune diseases has been estabiished, the Forssman shock can be said to be a useful means for testing a drug for autoimmune diseases. A drug effective for the treatment of Forssman shock is useful as a drug for autoimune diseases.

Anti-trypsin, anti-plasmin, anti-kallikrein and anti-thrombin activities.

The anti-trypsin, anti-plasmin, anti-kallikrein and anti-thrombin activities were determined according to the method of Muramatsu et al. [M. Muramatsu, T. Onishi, S. Makino, Y. Hayashi and S. Fujii, J. of Biochem., 58,214(1965)]. The results were as shown in Table 1. The data summarized in Table 1 are expressed in terms of molar concentration (ID50) of the test compound which inhibits 50% of the activity of each enzyme to hydrolyze TAME (tosylalginine methyl ester). The compound No. corresponds to the compound number shown in the Examples. The figure in parentheses shows the percentage inhibition at a concentration of the compound of 1 x 10-5M.

TABLE 1 Compound No. Trypsin Plasmin Kallikrein Thrombin 1 (35) (15) 5 x 10-6 (22) 2 2 x 10-6 8 x 10-7 3 x 10-7 9 x 10-7 3 1 x 10-7 5 x 10-7 9 x 10-7 3 x 10-7 4 4 x 10-6 (42) 6 x 10-6 8 x 10-6 5 3 x 10-7 5 x 10-7 5 x 10-7 2 x 10-7 6 4 x 10-6 3 x 10-6 4 x 10-7 2 x 10-6 7 2 x 10-6 7 x 10-7 4 x 10-7 2 x 10-6 8 2 x 10-6 8 x 10-7 4 x 10-7 1 x 10-6 9 9 x 10-7 6 x 10-6 (47) 1 x 10-6 10 4 x 10-8 3 x 10-6 4 x 10-7 2 x 10-7 11 3 x 10-6 2 x 10-6 4 x 10-7 4 x 10-7 12 3 x 10-7 4 x 10-7 3 x 10-7 5 x 10-7 14 1 x 10-6 2 x 10-6 5 x 10-7 7 x 10-7 15 2 x 10-7 3 x 10-7 4 x 10-7 6 x 10-7 16 1 x 10-6 1 x 10-6 4 x 10-7 4 x 10-7 17 8 x 10-7 2 x 10-6 1 x 10-6 7 x 10-7 18 9 x 10-7 5 x 10-7 5 x 10-7 5 x 10-7 19 2 x 10-7 3 x 10-7 7 x 10-7 2 x 10-7 23 5 x 10-7 2 x 10-6 3 x 10-6 4 x 10-6 25 7 x 10-7 6 x 10-7 2 x 10-6 3 x 10-6 26 3 x 10-7 6 x 10-7 3 x 10-6 2 x 10-6 28 4 x 10-6 9 x 10-6 4 x 10-6 (46) 31 2 x 10-8 4 x 10-7 4 x 10-7 1 x 10-6 33 5 x 10-7 4 x 10-7 4 x 10-6 3 x 10-6 34 6 x 10-7 2 x 10-6 3 x 10-7 5 x 10-7 35 8 x 10-6 3 x 10-6 9 x 10-7 3 x 10-6 TABLE 1 (Cont'd) 36 2 x 10-7 6 x 10-7 6 x 10-7 3 x 10-7 37 7 x 10-7 4 x 10-7 4 x 10-7 9 x 10-7 38 5x10-7 4x10-7 3x107 8x10-8 39 8 x 107 4 x 10-7 5 x 10-7 2 x 10-6 Anti-complement activity (1) Anti-CI (Cl?, CFs) activity and inhibition of complement mediated hemolysis: The anti-Cl esterase (Clr, Cls) activity was determined according to the method of Okamura et al. [K.

Okamura, M. Muramatsu and B. Fujii, Biochem. Biophys. Acta,295, 252-257 (1973)]. The inhibition of complement mediated hemolysis was determined according to the method of Baker at al. [B.R. Baker and E.H. Erickson, J. Med. Chem., 12,408-414 (1969)]. The results obtained were as shown in Table 2. The figures in Table 2 have the following meanings: Clr: Molar concentration of the test compound which inhibits 50% of the ability of Clr to hydrolyse AAME (acetylarginine methyl ester) (ID50).

Cls: Molar concentration of the test compound which inhibits 50% of the ability of Cls to hydrolyse ATEE (acetyltyrosine ethyl ester) (ID50).

The figure in parentheses shows the percent inhibition at a concentration of the compound of lx 1 10-5M.

Inhibition of complement mediated hemolysis (%): The inhibitory activity is shown in terms of percent inhibition of the compound at varied concentrations.

Compound No.: The compound number shown in the Examples TABLE 2 Compound Anti-Cl activity Inhibition of complement IVO. me@@@@ @@@@@@@ @@@@ Clr Cls 1 x 10-5 1 x 10-6 1 x 10-7 1 2x10-6 3 x 10-6 100 99 75 2 1 x 10-6 1 x 10-6 100 100 91 3 7 x 10-7 3 x 10-7 100 100 99 4 2x106 3x10-7 100 100 59 5 1 x 10-6 3 x 10-7 100 100 96 6 5 x 10-7 1 x 10-6 100 100 100 7 1 x 10-6 2 x 10-6 100 100 98 8 8x10-7 2 x 10-6 100 100 98 9 4x10-7 3 x 10-6 100 100 94 10 5 x 10-6 3 x 10-7 100 100 91 11 5x10-7 5 x 10-7 100 100 43 12 1 x 10-7 3 x 10-7 100 100 93 14 7 x 10 7 3 x 10-7 100 100 28 15 3 x 10-7 4 x 10-7 100 100 99 16 4x10-7 3x10-7 100 100 97 17 5x10-7 2x106 100 800 93 TABLE 2 (Cont'd) 18 3x10-7 3 x 10-6 100 100 97 19 2x10-7 3x10-7 97 97 93 20 100 98 43 23 3 x 10-6 2 x 10-6 100 95 76 25 1 x 10-6 2x10-6 100 98 82 26 5x10-7 4x10-6 100 98 93 28 2 x 10-6 3 x 10-6 100 82 35 31 2 x 10-7 3 x 10-7 100 98 97 33 7 x 10-7 2 x 10-6 97 97 81 34 5 x 10-7 5 x 10-7 100 100 58 35 2 x 10-6 3 x 10-6 100 100 71 36 5 x 10-7 4x10-6 100 100 68 37 3 x 10-6 4x10-7 99 78 12 38 3x10-7 3x10-5 100 100 98 39 4 x 10-7 4 x 10-6 100 100 71 (2) Forssman shock: The experiment was performed according to the method of l.G. Offerness et al. [Biochem. Pharmacol., 27 (14), 1873-1878 (1978)]. Male Hartlay guinea pigs of about 300 g in body weight were used.Each guinea pig of the control group was treated intravenously with hemolysin (minimum dose to cause the shock) (commercial hemolysin, 5,000 U as assayed by the method of Ogata) and the time elapsing until death was observed. For the test group, each guinea pig was treated intravenousiy with hemolysin after the administration of test compound (3 mg/kg) and the time elapsing until death was observed.

The results obtained were shown in Table 3.

TABLE 3 Control gro up Group treated (sec.) with compound Compound No. 1 Compound No. 31 278 Survival Survival 318 Survival Survival 296 Survival Survival Method of administration: A compound of the present invention is most suitably administered orally, though it can be administered by injection for example. It is used as a drug either alone or in combination with other drugs. It is administered generally in the form of a medicinal composition, though it can be administered as the simple substance without any additive. Examples of medicinal composition include tablets, powders, capsules, syrups and solutions. An oral composition may contain common additives such as binders, diluents, lubricants, disintegrators and excipients.An oral solution may be in the form of an aqueous or oily suspension, solution, emulsion, syrup or elixir, or in the form of a dry syrup which, before use, is mixed with water or other suitable solvent. The solutions may contain common additives such as suspending agents, flavoring agents, diluents, or emulsifiers. For injection, aqueous suspensions or oily suspensions may be used.

Dosage: A compound of the present invention may be administered to mammals (including man) orally at a dose of 10 to 200 mg per day or by intravenous injection at a dose of 1 to 20 mg per day. However, these doses are presented solely for the sake 6f example. A suitable dose for a patient should be determined depending upon the age and body weight of the patient and the features of the illness. An oral dosage unit may contain, for example, 50 to 100 mg of active ingredient, and an intravenous dosage unit 5 mg for example.

Examples of pharmaceutical formulations are described below.

Examples of pharmaceutical formulations: (1) Capsules: Compound of the invention 100.0 mg Lactose 59.0 Crystalline cellulose 33.4 Calcium carboxymethylcellulose 3.6 Magnesium stearate 4.0 Total 200.0 mg (2) Fine granules: Compound of the invention 50.0 mg Lactose 249.0 Mannitol 75.0 Corn starch 110.0 Hydroxypropylcellulose 16.0 Total 500.0 mg (3) Injections: Compound of the invention 5.0 mg Waterforinjection 2 ml Made up to injections in a customary manner.

Toxicity: The median lethal dose (LD50) of representative compounds of the present invention is as shown in Table 4.

TABLE 4 Compound LD50 mglkg (mouseJ No.

I.P. P;O.

1 100 2000 31 200 2500 Examples of preparation of the representative compounds of the present invention are described below.

The physical data of each compound are summarized in Table 5.

Table 5

KBr IR# cm-1 Compound # Salt mp C max No. (-COO-) 1 # 2MSA 145 (d) 61 2 # 2MSA 1720 (sinter) 3 # 2MSA 225 - 227 4 # 2MSA 1730 5 # 2HCl 249 - 250 - Cont'd - Table 5 (Cont'd)

70 6 # HCL.MSA 1720 (sinter) 7 # HCL.MSA 1730 8 # HAl.MSA 1730 9 # HCl.MSA 1720 10 # 2HCl 212 (d) 1715 63 11 # 2MSA 1730 (sinter) - Cont'd - Table 5 (Cont'd)

12 # MSA 200 - 203 13 # HCl 190 - 196 70 14 # 2MSA 1730 (sinter) 79 15 # 2MSA 1720 (sinter) 73 16 # 2MSA 1730 (sinter) 68 17 # 2MSA 1740 (sinter) 18 # MSA 1730 - Cont'd - Table 5 (Cont'd)

19 # MSA 180 - 183 20 # MSA 54 - 59 1700 21 # MSA 220 - 223 22 # MSA 1720 23 # HCl.MSA 217 (d) 24 # HCl.MAS 229 - 232 25 # HCl.MSA 178 - 183 26 # 3TsOH 198 - 202 - Con'd - Table 5 (Cont'd)

192 - 194 27 # MSA (d) 28 # 2HCl 181 - 184 215 - 218 29 # MSA (d) 30 # 2MSA 255 - 257 272 - 274 31 # 2HBr (d) 32 # 2HCl 110 - 113 231 - 234 33 # 2HBr (d) - Cont'd - Table 5 (Cont'd)

34 # 2HBr 1700 118 35 # 3HBr 1715 (sinter) 137 36 # 2TFA 1730 (sinter) 37 # MSA 262 (d) 1690 79 38 # 2HBr 1725 (sinter) 39 # 2HBr 1730 MAS shows methanesulfonate.

TsOH shows toluenesulfonate.

TFA shows trifluoroacetate.

Example 1 (Compound No. 1) Synthesis of 6-amidi no-2-naphthyl 5-guanidinomethyl-furan-2-carboxylate:

In a solvent mixture of 8 ml of dry N,N-dimethylformamide (DMF) and dry pyridine, were dissolved 2.0 g of 5-guanidinomethyl-furan-2-carboxylic acid methanesulfonate and 1.8 g of 6-amidino-2-naphthol methanesulfonate. To the resulting solution, while being cooled in ice, were added 1.8 g of DCC and a catalytic amount of 4-dimethylaminopyridine (DMAP). The mixture was stirred for 30 minutes with cooling in ice and then overnight at 30"C. The insolubles were removed by filtration and ethyl ether was added to the filtrate.

The supernatant was removed by decantation. The residue was dissolved in a small amount of methanol and the methanol solution was added dropwise to ethyl ether. After precipitation the supernatantwas removed by decantation. These procedures were repeated twice. Finally, the precipitate was collected by filtration and dried to obtain 1.2 g of a pale yellow substance of 6-amidino-2-naphthyl 5-guanidinomethyl-furan-2- carboxylate dimethanesulfonate.

Example 2 (Compound No. 2) Synthesis of 6-amidino-2-naphthyl 5-(2,3-dimethyl)guanidinomethyl4uran-2-carboxylate

In a solvent mixture of 2 ml of DMF and 2 ml of pyridine were dissolved 500 mg of 5-(2,3-dimethyl) guanidinomethyl-furan-2-carboxylic acid methanesulfonate, 360 mg of 6-amidino-2-naphthol methanesulfonate, 400 mg of DCC and a small amount of DMAP. The resulting solution was stirred overnight at room temperature. The insolubles were removed by filtration and ethyl ether was added to the filtrate. The resulting mixture was stirred. The precipitate was dissolved in a small amount of methanol and the methanol solution was added dropwise to ethyl acetate while stirring.The precipitate was collected by filtration to obtain 370 mg of 6-amidino-2-naphthyl 5-(2,3-dimethyl)guanidinomethylfuran-2-carboxylate dimethanesulfonate.

Compounds Nos. 3 to 30 were obtained as in Examples 1 and 2.

Example 3 (Compound No. 31) Synthesis of 6-amidi no-2-naphthyl 5-aminomethylthiophene-2-carboxylate

In 20 ml of a 30% HBr/acetic acid solution, was dissolved 1.0 g of 6-amidino-2-naphthyl 5benzyloxycarbonylaminomethylthiophene-2-carboxylate methanesulfonate. The solution was stirred for 30 minutes at room temperature. Ethyl ether was added to the resulting solution. The precipitate was collected by filtration and recrystallized from a mixture of methanol and ethyl ether to obtain 800 mg of 6-amidino-2-naphthyl 5-aminomethylthiophene-2-carboxylate dihydrobromide.

Compounds Nos. 32 to 39 were obtained as in Example 3.

Claims

1. Acompound of the general formula

wherein A represents a furan, thiophene or benzofuran group; R1 represents a hydrogen atom or a straight or branched chain alkyl group of 1 to 4 carbon atoms; R2 represents a hydrogen atom, a straight or branched chain alkyl group of 1 to 4 carbon atoms, an acyl group or

in which R3, R4 and R5, any two of which may be the same or different, each represents a hydrogen atom or a straight or branched chain alkyl group of 1 to 4 carbon atoms; or either R1 and R2, when R2 does not represent a nitrogen containing radical, or any two or more of radicals R1, R3, R4 and Rg, together with the nitrogen atoms to which they are attached, form a heterocyclic ring system, which may optionally contain other hetero atoms, and which may be unsubstituted or substituted; and n is 0, 1 or 2.

2. An amidino compound as claimed in claim 1, wherein R2 represents the radical

in which R3, R4 and R5, any two of which may be the same or different, each represents a hydrogen atom or a straight or branched chain alkyl group of 1 to 4 carbon atoms.

3. A compound as claimed in claim 1, wherein the acyl group represented by R2 is R6-CO-, wherein R5 represents a straight or branched chain alkyl group of 1 to 15 carbon atoms, a straight or branched chain alkoxy group of 1 to 4 carbon atoms, benzyloxy,

in which R7 and R8, which may be the same or different, each represents a hydrogen atom, a straight or branched chain alkvl group of 1 to 4 carbon atoms, benzyloxycarbonyl or another amino-protecting group, b represents -(CH2),- or

in which mis 1 or 2, and Rg represents

CH2OCH2- or NH2-(CH2)4-, any free amino group or amidino group being optionally protected, and any free amino group being optionally replaced by a nitro group.

4. A compound as claimed in any one of claims 1 to 3, wherein A represents furan.

5. An acid addition salt of a compound as claimed in any one of claims 1 to 4.

6. A physiologically tolerable acid addition salt of a compound as claimed in any one of claims 1 to 4.

7. A compound as claimed in claim 1, which is the free base corresponding to any one of compounds 1 to 39 shown in Table 5 herein.

8. An acid addition salt of a compound as claimed in claim 1, which is any of the compounds 1 to 39 shown in Table 5 herein.

9. A process for the preparation of a compound as claimed in claim 1 or an acid addition salt thereof which comprises a) reacting a compound of the general formula

in which R1, R2, A and n have the meanings given in claim 1, or a reactive intermediate or salt thereof with a compound of the general formula

or an acid addition salt thereof or with a corresponding compound in which the amidino group is protected, and, if required, splitting off the amidino protecting group, or b) in compound of the general formula

in which R1, R2, A and n have the meanings given above and Y represents a protected amidino group, removing the amidino protecting group from the radical represented by Y, and, if desired, converting a compound of the general formula (I) into another such compound or into an acid addition salt thereof, or converting an acid addition salt into a compound of the general formula (I).

10. A process as claimed in claim 9, wherein a compound of the general formula (I) having a protected amino or amidino group is converted into the corresponding compound having a free amino or amidino group, and/or a compound having a nitro group is reduced to form a compound having an amino group.

11. A process as claimed in claim 9, carried out as described in Example 1 or Example 2 herein and/or with reference to any one of compounds 1 to 39 herein.

12. A process as claimed in claim 10, wherein the removal of an amino protecting group is carried out substantially as described in Example 3 herein.

13. A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 9 to 12.

14. An acid addition salt of a compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 9 to 12.

15. A physiologically tolerable acid addition salt of a compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 9 to 12.

16. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 4,6 to 8, 13 and 15, in admixture or conjunction with a pharmaceutically suitable carrier.

17. A pharmaceutical preparation as claimed in claim 16, which is in dosage unit form.

18. A pharmaceutical preparation as claimed in claim 16 or claim 17, which is in a form suitable for oral administration.

19. A pharmaceutical preparation as claimed in claim 18, which contains in the range of from 50 to 100 mg of active ingredient per dosage unit.

20. A pharmaceutical preparation as claimed in claim 16 or claim 17, which is in a form suitable for intravenous administration.

21. A pharmaceutical preparation as claimed in claim 20, which contains substantially 5 mg of active ingredient per dosage unit.

22. A pharmaceutical preparation as claimed in claim 16, having a composition substantially as described in any one of the formulation Examples 1 to 3 herein.

23. A compound as claimed in any one of claims 1 to 4,6to 8, 13 and 15, ora pharmaceutical preparation as claimed in any one of claims 16 to 22, for use in a method of treatment of the human or animal body.

24. A compound of the general formula (I') shown in claim 9, wherein R1, R2, A and n have the meanings given in claim 1 and Y represents a protected amidino group.